The present invention relates to a novel piperidine derivative and use of the piperidine derivative for pharmaceutical preparations. Abnormalities in the central 5-HT controlling function and peripheral 5-HT controlling function are considered to induce various diseases such as mental disorders, circulatory system disorders and alimentary canal dysfunction, and it has been suggested that 5-HT7 is involved in those diseases. The compounds of the present invention are advantageous because they exhibit such a high affinity for the 5-HT7 that they can act thereon as any of an agonist, partial agonist or antagonist, and therefore, they can serve as the drugs for treating or preventing the above-mentioned diseases.
As the social environments have become more and more complicated recent years, lots of people are subject to excessive stresses. This situation has increased the number of patients suffering from the irritable bowel syndrome characterized by the leading symptoms such as abnormal bowel movement, abdominal pain and the like. To alleviate such symptoms, many drugs are used, for example, anticholinergics, laxatives, antidiarrheals, drugs for controlling intestinal functions, paralyzant acting on the mucous membranes, drugs for controlling gastrointestinal motility, autonomics, herbal medicines, anxiolytic agents, antidepressants, hyphotics, antipsychotic agents and the like.
The visceral pain and abdominal pain, which are usually important biological information that can transmit the visceral and abdominal pathoses to the individual include not only the pains appearing as the symptoms associated with the above-mentioned bowel disease, that is, irritable bowel syndrome, but also the pains caused by sudden contraction and convulsion of the tube-shaped organs such as stomach, gallbladder and the like and inflammation of the peritoneum and pleura. Antispasmodics and anti-inflammatory agents are used to reduce the latter pains.
However, the above-mentioned drugs are not necessarily satisfactory in light of their insufficient clinical efficacy and some side effects. Accordingly, there is an increasing demand for development of a drug of a new type capable of exhibiting excellent therapeutic effects without any side effect.
Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in the physiological or ethological processes. In particular, 90% of 5-HT exists in the enterochromaffin cells, so that the actions of 5-HT in the intestinal tract are physiologically and pathophysiologically significant. Fourteen types of 5-HT receptors have been identified up to date. The 5-HT7 receptor is the latest one among those 5-HT receptors, and expression of the 5-HT7 in the peripheral tissues of the coronal blood vessel and intestinal tract is reported (for example, see J. Biol. Chem., 268, pp 23422 (1993)).
The 5-HT7 receptor forms a conjugated system with G protein (Gs) that works to promote the production of cyclic adenosine monophosphate (cAMP). Therefore, stimulation of the serotonin leads to the increase in cAMP concentration in the cells via the 5-HT7 receptor (refer to, for example, J. Pharmacol. Exp. Ther., 287, pp 508 (1998)). As a result, for example, relaxation reaction is observed in the intestinal smooth muscle (refer to, for example, British J. Pharmacol., 128, pp 849 (1999)). In light of the above-mentioned background, it is reported that the 5-HT7 receptor antagonist has the potential for effectively treating various diseases considered to result from the abnormal conditions in the central and peripheral 5-HT controlling functions, for example, mental disorders (manic-depressive psychosis, anxiety, schizophrenia, epilepsy, somnipathy, disorders of biorhythm, migraine and the like); circulatory system disorders (hypertension and the like); and dysfunction of alimentary canal, as disclosed in, for example, Japanese Patent Unexamined Publication (JP Kokai) Hei 11-189585. Further, the therapeutic effects in a model of cerebral artery occlusion in rats are disclosed in, for example, WO200037082. In consideration of the presence of the 5-HT7 receptor on the intestinal tract tissues, some compounds having an affinity for the 5-HT7 hold promise of showing effectiveness against the irritable bowel syndrome, abdominal pain or visceral pain, and the like which are accompanied by the abnormal movement of the alimentary canal induced by the stimulation of serotonin.
However, no compound has been practically used for the treatments at the present stage on the grounds of lack of absorption by oral administration, problems in pharmacokinetics, and so on.
The scope of the present invention does not include the following compounds (i) through (iv) which are shown in British Patent Publication No. 1542823, U.S. Pat. No. 3,759,928, International Patent Publication WO 9218505, U.S. Pat. No. 3,687,956, International Patent Publication WO 9828275, Boll. Chim. Farm., 101, pp 365-375 (1962), and J. Med. Chem., 43, (21), pp 3895-3905 (2000). The compounds described in the above-mentioned references are different from those of the present invention in the mechanism and the target diseases.
wherein    (i) E1 is H—, HO— or PhCOO—, E2 is H—, HO— or PhCOO—, and E3 is H—, HO—, PhCOO— or tert-butyl;    (ii) E4 is methyl group or propylene group having a substituent at the 3-position;    (iii) E5 is HO—CH2CH2—, HO—CH2CH2OCH2CH2—, or H—; and    (iv) compound represented by formula (iv).